Cell Death & Disease
·
2024
·Vol. 15
·期 11
·1-12
·
IF 8.1
Zhang Jin,Maimaiti Aynuer,Chang Xihan,Sun Pengcheng,Chang Xiaohan
Cervical cancer is a leading cause of cancer-related death among women and its recurrence and metastasis poses challenges to treatment. Discoidin domain receptor 1 (DDR1) was associated with cellular migration and invasion in several types of cancers. However, its function in cervical cancer is still unclear. In this study, we found that DDR1 was significantly more expressed in cervical cancer samples than in normal tissues. SRY-Box transcription factor 2 (SOX2), a known oncogene in cervical cancer, showed a positive correlation with DDR1 and regulated DDR1 transcription, contributing to the elevated expression of DDR1 in cervical cancer. Regarding the function of DDR1 in cervical cancer, the overexpression of DDR1 caused an increase in the migration, invasion, and epithelial-mesenchymal transition (EMT) of cervical cancer cells. In contrast, cervical cancer cells with reduced DDR1 expression exhibited a lower migration rate, fewer invasive cells, and decreased levels of EMT markers. In vivo, mice injected with cervical cancer cells with overexpressed DDR1 showed more pulmonary metastasis and nodule number. Opposite results were found in mice injected with DDR1 silenced cervical cancer cells. Since DDR1 can cause phosphorylation of downstream targets, a phosphorylation omics was employed to reveal the downstream targets of DDR1, including eukaryotic translation initiation factor 4E binding protein 1 and EPH receptor A2. Furthermore, DDR1 bound directly with Src homology 2 domain of growth factor receptor bound protein 2 (GRB2) which mediated the function of DDR1 in the malignant behaviors of cervical cancer and the phosphorylation of downstream targets. In conclusion, DDR1 binds directly to GRB2 and then affects downstream phosphorylation signals, ultimately exacerbating the metastasis of cervical cancer cells. This work sheds light on the mechanism by which DDR1 functions in cervical cancer cells, providing therapeutic strategy for the treatment of cervical cancer.
研究领域:
肿瘤学
·
分子生物学
·
癌症生物学
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产品关联
DOI
PubMed
高影响因子
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
·
2025
·Vol. 51
·期 1
·285-297
·
IF 1.7
Xu Xuemei,Chen Siyu,Sun Doudou,Wang Xuebao,Xu Zhouyang
Objective: The discoidin domain receptor-1 (DDR1) has been demonstrated as a potential target in gefitinib-resistant non-small cell lung cancer (NSCLC). However, drug development in this area remains limited. Therefore, this study aims to chemically synthesize novel DDR1 inhibitors and explore their activity against gefitinib-resistant NSCLC. Methods: The structures of the synthesized compounds were confirmed by electrospray ionization mass spectrometry (ESI-MS), 1 H, 13 C NMR, and elemental analysis, followed by kinase screening experiments. The inhibitory impact of these compounds on the proliferation of PC-9 cells and gefitinib-resistant cell lines (PC-9GR and HCC827GR) was evaluated using the cell counting kit-8 (CCK-8) assay. Furthermore, the invasion capability of the cells was assessed using the Transwell assay. Additionally, Western blot analysis was employed to explore the targeting effects of these compounds on DDR1. Results and Discussion: Twenty-four 4,6-disubstituted pyrimidine derivatives were synthesized in series A, B, and C. Some compounds in series A and C exhibited promising inhibitory effects against DDR1 and DDR2, with compounds ( A04 ), ( A05 ), and ( C04 ) demonstrating more pronounced activities. Moreover, compounds ( A02 ), ( A03 ), ( A07 ), and ( C04 ) significantly impeded the viability of PC-9 and PC-9GR cells, with ( A07 ) exhibiting the strongest inhibition, with half-maximal inhibitory concentration (IC 50 ) values of 1.12 ± 0.07, 1.03 ± 0.18, and 1.56 ± 0.19 µM against PC-9, PC-9GR, and HCC827GR cells, respectively. Furthermore, 1 µM of ( A03 ) and ( A07 ) significantly inhibited the protein expression of p -DDR1 and DDR1, with compound ( A07 ) being the most significant inhibitor ( p < 0.001). Additionally, the Transwell assay demonstrated that 1 µM of ( A07 ) substantially inhibited the invasion of PC-9 ( p = 0.0003) and PC-9GR cells ( p = 0.0019). Conclusions: The newly synthesized DDR1 inhibitor ( A07 ) effectively inhibits the proliferation and invasion of gefitinib-resistant NSCLC cells, offering a potential new therapeutic option for treating NSCLC.
研究领域:
肿瘤学
·
药物化学
·
分子生物学
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DOI
高影响因子
Advanced Science
·
2024
·
IF 14.3
Guangman Cui,Shaohui Deng,Biao Zhang,Manchun Wang,Zhousheng Lin,Xinyue Lan,Zelong Li,Guangyu Yao,Meng Yu,Jun Yan
The extracellular matrix (ECM) is critical for drug resistance in colorectal cancer (CRC). The abundant collagen within the ECM significantly influences tumor progression and matrix-mediated drug resistance (MMDR) by binding to discoidin domain receptor 1 (DDR1), but the specific mechanisms by which tumor cells modulate ECM via DDR1 and ultimately regulate TME remain poorly understand. Furthermore, overcoming drug resistance by modulating the tumor ECM remains a challenge in CRC treatment. In this study, a novel mechanism is elucidated by which DDR1 mediates the interactions between tumor cells and collagen, enhances collagen barriers, inhibits immune infiltration, promotes drug efflux, and leads to MMDR in CRC. To address this issue, a multistage drug delivery system carrying DDR1-siRNA and chemotherapeutic agents is employed to disrupt collagen barriers by silencing DDR1 in tumor, enhancing chemotherapy drugs diffusion and facilitating immune infiltration. These findings not only revealed a novel role for collagen-rich matrix mediated by DDR1 in tumor resistance, but also introduced a promising CRC treatment strategy.
研究领域:
肿瘤学
·
药学
·
生物医学工程
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2026
·Vol. 27
·期 11
·5135
·
IF 5.6
Mengyuan Fan,Yuchen Sun,Ruyi Mei,Wenwen Lu,Xiaofeng Zhao,Aifeng Yang,Mengsheng Qiu
In peripheral nervous system (PNS), immature Schwann cells differentiate into two functionally distinct types of mature Schwann cells: myelinating Schwann cells, which establish a one-to-one relationship with large-diameter axons and initiate the complex myelination program that enables the rapid saltatory conduction of nerve impulses, and non-myelinating Schwann cells, which envelop multiple small-diameter axons without forming myelin, but support axon survival and maintain microenvironment homeostasis. Here, we demonstrate that discoidin domain receptor 1 (DDR1) signaling plays a pivotal role in Schwann cell maturation and peripheral nerve myelination.Ddr1−/−mice of both sexes exhibited fewer myelinating Schwann cells and profound hypomyelination, reduced nerve conduction velocity, and apparent motor dysfunction. Expression of myelin markers was markedly reduced in the mutants accompanied by the formation of abnormal myelin ultrastructure resembling “onion bulbs”. Mechanistically,Ddr1deficiency impaired Schwann cell myelination through the marked hyperactivation of the MAPK/ERK signaling pathway. These findings establish DDR1 as a novel regulator of Schwann cell myelination and highlight its potential as a therapeutic target for demyelinating neuropathies.
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DOI
PubMed
高影响因子
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